4-aminopyrimidine derivatives

ABSTRACT

This invention is 4-aminopyrimidine derivatives of the formula  
                 
 
     wherein R 1 , R 2 , R 3  and R 4  are as defined in the specification or a pharmaceutically acceptable salt thereof. The invention also is the preparation of compounds of formula I, pharmaceutical compositions containing therapeutically effective amounts of compounds of formula I or pharmaceutically acceptable salts thereof and to a method of treatment comprising administering therapeutically effective amounts of the compound of formula I for the prevention or treatment of mGluR5 receptor mediated disorders.

FIELD OF INVENTION

[0001] The present invention relates to 4-aminopyrimidine derivatives ofthe formula

[0002] Compounds of formula I are metabotropic glutamate (mGluR 5a)receptor antagonists and are useful in the treatment of disordersresponsive to mediation of the mGluR 5a receptors.

BACKGROUND

[0003] In the central nervous system (CNS) the transmission of stimulitakes place by the interaction of a neurotransmitter, which is sent outby a neuron, with a neuroreceptor.

[0004] Glutamate is the major excitatory neurotransmitter in the brainand plays a unique role in a variety of central nervous system (CNS)functions. The glutamate-dependent stimulus receptors are divided intotwo main groups. The first main group, namely the ionotropic receptors,forms ligand-controlled ion channels. The metabotropic glutamatereceptors (mGluR) belong to the second main group and, furthermore,belong to the family of G-protein coupled receptors.

[0005] At present, eight different members of these mGluR are known andof these some even have sub-types. According to their sequence homology,signal transduction mechanisms and agonist selectivity, these eightreceptors can be sub-divided into three sub-groups:

[0006] mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong togroup II and GluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

[0007] Ligands of metabotropic glutamate receptors belonging to thefirst group can be used for the treatment or prevention of acute and/orchronic neurological disorders such as psychosis, epilepsy,schizophrenia, Alzheimer's disease, cognitive disorders and memorydeficits, as well as chronic and acute pain.

[0008] Other treatable indications in this connection are restrictedbrain function caused by bypass operations or transplants, poor bloodsupply to the brain, spinal cord injuries, head injuries, hypoxia causedby pregnancy, cardiac arrest and hypoglycaemia. Further treatableindications are ischemia, Huntington's chorea, amyotrophic lateralsclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy,idiopathic parkinsonism or parkinsonism caused by medicaments as well asconditions which lead to glutamate-deficiency functions, such as e.g.muscle spasms, convulsions, migraine, urinary incontinence, nicotineaddiction, opiate addiction, anxiety, vomiting, dyskinesia anddepressions.

[0009] Disorders mediated fully or in part by mGluR5 are for exampleacute, traumatic and chronic degenerative processes of the nervoussystem, such as Alzheimer's disease, senile dementia, Parkinson'sdisease, Huntington's chorea, amyotrophic lateral sclerosis and multiplesclerosis, psychiatric diseases such as schizophrenia and anxiety,depression and pain.

[0010] Selective mGluR5 antagonists are especially useful for thetreatment of anxiety and pain.

SUMMARY

[0011] The present invention is a compound of formula

[0012] or a pharmaceutically acceptable salt thereof, wherein

[0013] R¹ is selected from the group consisting of

[0014] C₂-C₆-alkenyl,

[0015] C₂-C₆-alkinyl,

[0016] C₃-C₆-cycloalkyl,

[0017] —C(O)O—(C₁-C₆)-alkyl,

[0018] —C(O)O—(C₂-C₆)-alkenyl,

[0019] —C(O)O—(C₂-C₆)-alkinyl,

[0020] —C(O)O—(C₃-C₆)-cycloalkyl,

[0021] —C(O)O—CH₂-(C₃-C₆)-cycloalkyl,

[0022] —C(O)O—(C₃-C₆)-cycloalkyl substituted by at least oneC₁-C₆-alkyl,

[0023] —C(O)O—CH₂—(C₃-C₆)-cycloalkyl, substituted by at least oneC₁-C₆-alkyl,

[0024] —C(O)O—CH₂-heteroaryl,

[0025] —C(O)O—CH₂-heteroaryl substituted by at least one substitutentselected from the group C₁-C₆-alkyl, unsubstituted heteroaryl andheteroaryl substituted by at least one substituent selected from thegroup consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl,C₃-C₆-cycloalkyl and halogen;

[0026] R² is hydrogen or C₁-C₆-alkyl;

[0027] R³ is selected from the group consisting of

[0028] unsubstituted aryl, aryl substituted by at least one substituentselected from the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkinyl, C₃-C₆-cycloalkyl, halogen, and cyano, unsubstitutedheteroaryl and heteroaryl substituted by at least one substituentselected from the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkinyl, C₃-C₆-cycloalkyl, halogen, cyano, and—C(O)O—(C₁-C₆)-alkyl;

[0029] R⁴ is hydrogen or C₁-C₆-alkyl; and

[0030] m is 0, 1 or 2.

[0031] It has now surprisingly been found that the compounds of formulaI are metabotropic glutamate receptor antagonists. Compounds of formulaI are distinguished by having valuable therapeutic properties. They canbe used in the treatment or prevention of mGluR5 receptor mediateddisorders.

[0032] One object of the present invention is compounds of formula I andpharmaceutically acceptable salts thereof. A further object is thepreparation of the compounds of formula I and pharamceuticallyacceptable salts thereof. Pharmaceutical compositions containing atherapeutically effective amount of a compound of formula I or apharmaceutically acceptable salts thereof, and their manufacture arealso an object of the present invention. Another object of the presentinvention is a method of treatment, control or prevention of mGluR5receptor mediated disorders, comprising administering a therapeuticallyeffective amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof to a person in need of such treatment. The mostpreferred indication in accordance with the method of treatment of thepresent invention is the treatment or alleviation of anxiety and pain.

DETAILED DESCRIPTION

[0033] The following definitions of general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination.

[0034] The term “(C₁-C₆)-alkyl” (“lower alkyl”) used in the presentdescription denotes straight-chain or branched saturated hydrocarbonresidues with 1 to 6 carbon atoms, preferably with 1 to 4 carbon atoms,such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl and thelike.

[0035] The terms “C₂-C₆-alkenyl” or “C₂-C₆-alkinyl” denotestraight-chain or branched unsaturated hydrocarbon residues with 2 to 6carbon atoms, preferably with 2 to 4 carbon atoms, such as ethenyl,ethinyl, 1-propenyl, 2-propenyl, propargyl, 1-butenyl and the like.

[0036] The terms “unsubstituted” and “substituted” are used in the samecontext as generally used in organic chemistry.

[0037] The term “C₃-C₆-cycloalkyl” means a cycloalkyl group containing 3to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl.

[0038] The term “halogen” denotes fluorine, chlorine, bromine andiodine.

[0039] “Aryl” represents an aromatic carbocyclic group consisting of oneindividual ring, or one or more fused rings in which at least one ringis aromatic in nature. Preferred aryl groups are phenyl or naphthyl.

[0040] The term “heteroaryl” refers to an aromatic 5- or 6-membered ringcontaining one or more heteroatoms selected from nitrogen, oxygen orsulphur, or to a fused-ring aromatic group comprising two 5- or6-membered rings, in which one or both rings can contain one or moreheteroatoms selected from nitrogen, oxygen or sulphur. Examples of suchheteroaryl groups are furyl, pyrrolyl, thienyl (thiophenyl),1H-imidazolyl, 2H-imidazolyl, 4H-imidazolyl, 1H-pyrazolyl, 3H-pyrazolyl,4H-pyrazolyl, 1,2-oxazolyl, 1,3-oxazolyl, [1,2,4]triazolyl,[1,2,3]triazolyl, [1,2,4] oxadiazolyl, [1,3,4]oxadiazolyl,[1,2,3]oxadiazolyl, tetrazolyl, [1,2,3,4]oxatriazolyl,[1,2,3,5]oxatriazolyl, 1,3-thiazolyl, 1,2-thiazolyl, pentazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuryl (benzofuranyl),benzothienyl (benzothiophenyl), benzimidazolyl, benzo [1,4] dioxinyl,benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, quinolyl, isoquinolyland the dihydro derivatives of said 5- or 6-membered heteroaromaticrings.

[0041] Preferred heteroaryl groups are furyl, pyrrolyl and thienyl aswell as [1,2,4]oxadiazolyl or isoxazolyl.

[0042] The term “pharmaceutically acceptable salt” refers to any saltderived from a pharmaceutically acceptable inorganic or organic acid orbase.

[0043] Preferred compounds of formula I are those in which m is 0 or 1.Especially preferred are those compounds in which m is 1.

[0044] More preferred are compounds of formula I in which m is 1 and R³is selected from the group consisting of unsubstituted heteroaryl andheteroaryl substituted by at least one substituent selected from thegroup consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl,C₃-C₆-cycloalkyl, halogen or cyano.

[0045] The following are more preferred compounds of formula I in whichm is 1, R³ signifies unsubstituted heteroaryl or heteroaryl substitutedby at least one C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl,C₃-C₆-cycloalkyl, halogen or cyano, and R¹ is —C(O)O—(C₁-C₆)-alkyl,—C(O)O—(C₂-C₆)-alkenyl, —C(O)O—(C₂-C₆)-alkinyl,—C(O)O—(C₃-C₆)-cycloalkyl, —C(O)O—CH₂-(C₃-C₆)-cycloalkyl,—C(O)O—(C₃-C₆)-cycloalkyl, or —C(O)—CH₂-(C₃-C₆)-cycloalkyl wherein thecycloalkyl ring is substituted by at least one C₁-C₆-alkyl,—C(O)O—CH₂-heteroaryl or —C(O)O—CH₂-heteroaryl substituted by at leastone C₁-C₆-alkyl. The compounds are selected from the group consisting of(4-amino-5-thiophen-2-ylmethyl-pyrimidin-2-ylsulfanyl)-acetic acidmethyl ester,(4-amino-5-thiophen-2-ylmethyl-pyrimidin-2-ylsulfanyl)-acetic acid ethylester, [4-amino-5-(1-methyl-1H-pyrrol-2-ylmethyl)-pyrimidin-2-ylsulfanyl]-acetic acid ethyl ester,2-(4-amino-5-thiophen-2-ylmethyl-pyrimidin-2-ylsulfanyl)-propionic acidmethyl ester,(4-amino-5-thiophen-3-ylmethyl-pyrimidin-2-ylsulfanyl)-acetic acid ethylester, (4-amino-5-furan-3-ylmethyl-pyrimidin-2-ylsulfanyl)-acetic acidethyl ester, [4-amino-5-(3-methyl-thiophen-2-ylmethyl)-pyrimidin-2-ylsulfanyl]-acetic acid ethyl ester,[4-amino-5-(5-chloro-thiophen-2-ylmethyl)-pyrimidin-2-ylsulfanyl]-aceticacid ethyl ester,[4-amino-5-(5-ethyl-furan-2-ylmethyl)-pyrimidin-2-ylsulfanyl]-aceticacid ethyl ester,[4-amino-5-(5-methyl-furan-2-ylmethyl)-pyrimidin-2-ylsulfanyl]-aceticacid ethyl ester,(4-ethylamino-5-thiophen-2-ylmethyl-pyrimidin-2-ylsulfanyl)-acetic acidethyl ester, and(4-isobutylamino-5-thiophen-2-ylmethyl-pyrimidin-2-ylsulfanyl)-aceticacid ethyl ester.

[0046] Further preferred are those compounds of formula I in which m is1, R³ signifies unsubstituted heteroaryl or heteroaryl substituted byone or more C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₃-C₆-cycloalkyl,halogen or cyano, and R¹ signifies unsubstituted heteroaryl orheteroaryl substituted by one or more C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkinyl, C₃-C₆-cycloalkyl or halogen. An example of such acompound is2-([1,2,4]Oxadiazol-3-ylmethylsulfanyl)-5-thiophen-2-ylmethyl-pyrimidin-4-ylamine.

[0047] Especially preferred also are compounds of formula 1 in which mis 1, R³ signifies unsubstituted heteroaryl or heteroaryl substituted byone or more C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₃-C₆-cycloalkyl,halogen or cyano, and R¹ signifies C₂-C₆-alkenyl, C₂-C₆-alkinyl orC₃-C₆-cycloalkyl. Examples of these compounds are selected from thegroup consisting of2-prop-2-ynylsulfanyl-5-thiophen-2-ylmethyl-pyrimidin-4-ylamine,2-allylsulfanyl-5-thiophen-2-ylmethyl-pyrimidin-4-ylamine, and2-cyclopropylmethylsulfanyl-5-thiophen-2-ylmethyl-pyrimidin-4-ylamine.

[0048] Also preferred are compounds of formula I in which m is 1 and R³is unsubstituted aryl or aryl substituted by at least one substituentselected from the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkinyl, C₃-C₆-cycloalkyl, halogen and cyano.

[0049] Especially preferred are compounds of formula I in which m is 1,R³ is selected from the group consisting of unsubstituted aryl and arylsubstituted by at least one substituent selected from the groupconsisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl,C₃-C₆-cycloalkyl, halogen and cyano, and R¹ is —C(O)O—(C₁-C₆)-alkyl,—C(O)O—(C₂-C₆)-alkenyl, —C(O)O—(C₂-C₆)-alkinyl,—C(O)O—(C₃-C₆)-cycloalkyl, —C(O)O—CH₂-(C₃-C₆)-cycloalkyl,C(O)O—(C₃-C₆)-cycloalkyl or —C(O)O—CH₂-(C₃-C₆)-cycloalkyl substituted byat least one substituent selected from the group consisting ofC₁-C₆-alkyl, —C(O)O—CH₂-heteroaryl and C(O)O—CH₂-heteroaryl substitutedby at least one C₁-C₆-alkyl. The following are examples of suchcompounds selected from the group consisting of(4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid ethyl ester,[4-amino-5-(4-bromo-benzyl)-pyrimidin-2-ylsulfanyl]-acetic acid ethylester, (4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid allylester, (4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid prop-2-ynylester, (4-amino-5-benzyl-pyrimidin-2-ylsulfanyl) -acetic acid2-methyl-cyclopropylmethyl ester,(4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid cyclobutylmethylester, (4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid cyclobutylester, (4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid cyclopentylester, (4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid5-methyl-isoxazol-3-ylmethyl ester,(4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid cyclopropylmethylester, and (4-amino-5-benzyl-pyrimidin-2-yloxy)-acetic acid methylester.

[0050] Additional preferred compounds of formula I are those in which mis 1, R³ is unsubstituted aryl or aryl substituted by at least onesubstituent selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₃-C₆-cycloalkyl, halogen and cyano: andR¹ is unsubstituted heteroaryl or heteroaryl substituted by at least onesubstituent selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₃-C₆-cycloalkyl and halogen. Exemplary ofthis class of preferred compound is5-Benzyl-2-(3-cyclopropyl-[1,2,4]oxadiazol-5-ylmethylsulfanyl)-pyrimidin-4-ylamine.

[0051] Further preferred compounds of formula I are those in which m is1, R³ is unsubstituted aryl or aryl substituted by at least onesubstituent selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₃-C₆-cycloalkyl, halogen and cyano; andR¹ is selected from the group consisting of C₂-C₆-alkenyl, C₂-C₆-alkinyland C₃-C₆-cycloalkyl. Exemplary of such a compound is4-(2-Allylsulfanyl-4-amino-pyrimidin-5-ylmethyl)-benzonitrile.

[0052] Also preferred are compounds of formula I in which m is 1 and R³signifies C₃-C₆-cycloalkyl. An example of such a compound is(4-amino-5-cyclopropylmethyl-pyrimidin-2-yl-sulfanyl)-acetic acid ethylester.

[0053] Further preferred compounds of formula I are those in which m is0. Especially preferred are those, in which m is 0 and R¹ is selectedfrom the group consisting of —C(O)O—(C₁-C₆)-alkyl,—C(O)O—(C₂-C₆)-alkenyl, —C(O)O—(C₂-C₆)-alkinyl,—C(O)O—(C₃-C₆)-cycloalkyl, —C(O)O—CH₂-(C₃-C₆)-cycloalkyl,—C(O)O—(C₃-C₆)-cycloalkyl or —C(O)O—CH₂-(C₃-C₆)-cycloalkyl substitutedby at least one C₁-C₆-alkyl, —C(O)O—CH₂-heteroaryl and—C(O)O—CH₂-heteroaryl substituted by at least one C₁-C₆-alkyl. Thefollowing compounds selected from the group consisting of[4-amino-5-(2,4-dichloro-phenyl)-pyrimidin-2-ylsulfanyl]-acetic acidethyl ester,4-amino-2-ethoxycarbonylmethylsulfanyl-pyrimidine-5-carboxylic acidethyl ester, and[4-amino-5-(2-chloro-phenyl)-pyrimidin-2-ylsulfanyl]-acetic acid ethylester are exemplary of such compounds.

[0054] Preferred compounds of formula I are those in which R² ishydrogen.

[0055] Also preferred are compounds of formula I, wherein R⁴ signifieshydrogen.

[0056] Preferred compounds of formula I are also those wherein R³signifies a heteroaryl group selected from unsubstituted furyl, pyrrolyland thienyl and furyl, pyrrolyl and thienyl substituted by substitutedby at least one substituent selected from C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkinyl, C₃-C₆-cycloalkyl, halogen and cyano.

[0057] Also preferred are compounds of formula I wherein R¹ signifies[1,2,4] oxadiazolyl optionally substituted by at least one substituentselected from the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkinyl, C₃-C₆-cycloalkyl or halogen.

[0058] The compounds of formula I and their pharmaceutically acceptablesalts can be manufactured by reacting a compound of formula

[0059] wherein R⁵ signifies phenylamino, 3-thienylamino or morpholino,and R³ and m have the significances as defined before,

[0060] with thiourea to obtain a compound of formula

[0061] and reacting this compound with a compound of formula

[0062] wherein R¹ and R² have the significances as defined before and Xis halogen, and, if desired, converting the amino group into anaminoalkyl group, thereby forming a compound of formula

[0063] wherein R⁴ is hydrogen or C₁-C₆-alkyl,

[0064] and, if desired, converting a compound of formula I into apharmaceutically acceptable salt.

[0065] In accordance with the invention, a 4-aminopyrimidine derivativeof formula III is formed by condensation of thiourea (1.1 eq.) with anappropriately substituted compound of formula II. Compounds of formulaIII, wherein m signifies 1 or 2, are prepared from thiourea and a2-substituted 3-phenylamino-acrylonitrile. The condensation reaction iscarried out in ethanol under reflux using a catalytic amount of a strongbase like sodium ethoxide (e.g. 0.1 eq). The product can be obtained asprecipitate after reducing the solvent and cooling (Scheme 1).

[0066] The 2-substituted 3-phenylamino-acrylonitrile of formula IIa,wherein n is 1 or 2, is prepared by condensation of an aldehyde offormula VII, wherein p is 0 or 1, with β-anilinopropionitrile (VI)(scheme 2). Treatment of a solution of VII and VI in dimethylsulfoxidewith strong base like potassium-tert-butylate (1 eq.) gives thecondensation product IIa.

[0067] 4-Aminopyrimidines of formula III, wherein m signifies 0, areobtained by the procedures described in schemes 3 and 4.

[0068] For example, compounds of formula IIIb are prepared by reacting a2-formyl-2-phenylacetonitrile of formula VIII with morpholine followedby condensation of the obtained 3-morpholino-2-phenylacrylonitrile offormula IIb with thiourea (scheme 3).

[0069] A 4-amino-2-sulfanyl-pyrimidine-5-carboxylic acid ester offormula IIIc is obtained by condensation of a2-cyano-3-(3-thienylamino)-2-propenoic acid ester of formula IIc withthiourea (scheme 4).

[0070] The reaction of the 5-substituted 4-amino-pyrimidine-2-thiols offormula III with appropiate alkyl halides of formula IV leads to thecorresponding 5-substituted 2-alkylsulfanyl-pyrimidin-4-ylamines offormula Ia. The reaction is carried out at room temperature in a IMsolution of sodium methoxide in methanol or of sodium ethoxide inethanol (scheme 5).

[0071] Compounds of formula I, wherein R¹ is alkoxycarbonyl and R² ishydrogen, are prepared by either directly reacting a compound of formulaIII with an alkyl bromoacetate or by the procedure as described inscheme 6.

[0072] A 5-substituted (4-amino-pyrimidin-2-ylsulfanyl)-acetic acid offormula Ib is obtained by reacting a compound of formula III with2-chloro-acetic acid IX. Esterification of Ib withdicyclohexylcarbodiimide (DCC) and the appropiate alcohol R⁷OH, in whichR⁷ is (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkinyl,(C₃-C₆)-cycloalkyl, —CH₂-(C₃-C₆)-cycloalkyl or —CH₂-heteroaryl whereinthe heteroaryl ring maybe substituted by one or more (C₁-C₆)-alkyl,leads to the ester of formula Ic.

[0073] Compounds of formula I, wherein R⁴ signifies C₁-C₆-alkyl areprepared by reacting the amine of formula Ia with an appropriatealdehyde. For example, a compound of formula Id, wherein R⁴ is ethyl, isobtained by the reaction of a compound of formula Ia with acetaldehydeand reduction with sodium cyanoborohydride (scheme 7).

[0074] Pharmaceutically acceptable salts of compounds of formula I canbe manufactured readily according to methods known to one skilled in theart and taking into consideration the nature of the compound to beconverted into a salt. Pharmaceutically acceptable inorganic or organicacids such as, for example, hydrochloric acid, hydrobromic acid,sulphuric acid, nitric acid, phosphoric acid or citric acid, formicacid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaricacid, methanesulphonic acid, p-toluenesulphonic acid and the like aresuitable for the formation of pharmaceutically acceptable salts of basiccompounds of formula I. Compounds which contain the alkali metals oralkaline earth metals, for example sodium, potassium, calcium, magnesiumor the like, basic amines or basic amino acids are suitable for theformation of pharmaceutically acceptable salts of acidic compounds.

[0075] The compounds of formula I and their pharmaceutically acceptablesalts are, as already mentioned above, metabotropic glutamate receptorantagonists and can be used for the treatment or prevention of mGluR5receptor mediated disorders, such as acute and/or chronic neurologicaldisorders, cognitive disorders and memory deficits, as well as acute andchronic pain. Treatable neurological disorders are for instanceepilepsy, schizophrenia, anxiety, acute, traumatic or chronicdegenerative processes of the nervous system, such as Alzheimer'sdisease, senile dementia, Huntington's chorea, ALS, multiple sclerosis,dementia caused by AIDS, eye injuries, retinopathy, idiopathicparkinsonism or parkinsonism caused by medicaments as well as conditionswhich lead to glutamate-deficient functions, such as e.g. muscle spasms,convulsions, migraine, urinary incontinence, nicotine addiction,psychoses, opiate addiction, anxiety, vomiting, dyskinesia anddepression. Other treatable indications are restricted brain functioncaused by bypass operations or transplants, poor blood supply to thebrain, spinal cord injuries, head injuries, hypoxia caused by pregnancy,cardiac arrest and hypoglycaemia.

[0076] The compounds of formula I and their pharmaceutically acceptablesalts are especially useful as analgesics. Treatable kinds of paininclude inflammatory pain such as arthritis and rheumatoid disease,vasculitis, neuropathic pain such as trigeminal or herpetic neuralgia,diabetic neuropathy pain, causalgia, hyperalgesia, severe chronic pain,post-operative pain and pain associated with various conditions likecancer, angina, renal or billiay colic, menstruation, migraine and gout.

[0077] The pharmacological activity of the compounds was tested usingthe following method:

[0078] cDNA encoding rat mGlu 5a receptor was transiently transfectedinto EBNA cells using a procedure described by E.-J. Schlaeger and K.Christensen (Cytotechnology 1998, 15, 1-13). [Ca²⁺]i measurements wereperformed on mGlu 5a transfected EBNA cells after incubation of thecells with Fluo 3-AM (obtainable by FLUKA, 0.5 μM final concentration)for 1 hour at 37° C. followed by 4 washes with assay buffer (DMEMsupplemented with Hank's salt and 20 mM HEPES. [Ca²⁺]i measurements weredone using a fluorometric imaging plate reader (FLIPR, Molecular DevicesCorporation, La Jolla, Calif., USA). When compounds were evaluated asantagonists they were tested against 10 μM glutamate as agonist.

[0079] The inhibition (antagonists) curves were fitted with a fourparameter logistic equation giving IC₅₀, and Hill coefficient using theiterative non linear curve fitting software Origin (Microcal SoftwareInc., Northampton, Mass., USA).

[0080] The compounds of the present invention are mGluR 5a receptorantagonists. The activities of compounds of formula I as measured in theassay described above are in the range of 10 μM or less, typically of 1μM or less, and ideally of 0.2 μM or less.

[0081] In table I below are shown specific activity data of preferredcompounds of formula I as measured in the assay described above: TABLE IExample No. Compound name IC₅₀ (μM)  3(4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic 0.14 acid ethyl ester 4 [4-amino-5-(1-methyl-1H-pyrrol-2-ylmethyl)- 0.38pyrimidin-2-ylsulfanyl]-acetic acid ethyl ester  5[4-amino-5-(2,4-dichloro-phenyl)-pyrimidin-2- 3.85 ylsulfanyl]-aceticacid ethyl ester  6 [4-amino-5-(4-bromo-benzyl)-pyrimidin-2- 0.18ylsulfanyl]-acetic acid ethyl ester  82-prop-2-ynylsulfanyl-5-thiophen-2-ylmethyl- 1.39 pyrimidin-4-ylamine  92-allylsulfanyl-5-thiophen-2-ylmethyl-pyrimidin- 2.79 4-ylamine 112-([1,2,4]oxadiazol-3-ylmethylsulfanyl)-5- 0.4thiophen-2-ylmethyl-pyrimidin-4-ylamine 12(4-amino-5-thiophen-3-ylmethyl-pyrimidin-2- 0.18 ylsulfanyl)-acetic acidethyl ester 13 (4-amino-5-furan-3-ylmethyl-pyrimidin-2- 0.16ylsulfanyl)-acetic acid ethyl ester 194-amino-2-ethoxycarbonylmethylsulfanyl- 0.27 pyrimidine-5-carboxylicacid ethyl ester 21 (4-ethylamino-5-thiophen-2-ylmethyl-pyrimidin- 0.62-ylsulfanyl)-acetic acid ethyl ester 22(4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic 0.12 acid allyl ester24 (4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic 0.63 acid2-methyl-cyclopropylmethyl ester 25(4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic 1.46 acidcyclobutylmethyl ester 29(4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic 0.2 acidcyclopropylmethyl ester 31 4-isobutylamino-5-thiophen-2-ylmethyl- 0.16pyrimidin-2-ylsulfanyl)-acetic acid ethyl ester 325-benzyl-2-(3-cyclopropyl-[1,2,4]oxadiazol-5- 0.45ylmethylsulfanyl)-pyrimidin-4-ylamine

[0082] The compounds of formula I and pharmaceutically acceptable saltsthereof can be used as pharmaceutical compositions. The pharmaceuticalcompositions can be administered orally, e.g. in the form of tablets,coated tablets, dragées, hard and soft gelatin capsules, solutions,emulsions or suspensions. However, the administration can also beeffected rectally, e.g. in the form of suppositories, or parenterally,e.g. in the form of injection solutions.

[0083] A therapeutically effective amount of the compounds of formula Iand pharmaceutically acceptable salts thereof can be processed withpharmaceutically inert, inorganic or organic carriers for the productionof pharmaceutical compositions. Lactose, corn starch or derivativesthereof, talc, stearic acid or its salts and the like can be used, forexample, as such carriers for tablets, coated tablets, dragées and hardgelatin capsules. Suitable carriers for soft gelatin capsules are, forexample, vegetable oils, waxes, fats, semi-solid and liquid polyols andthe like; depending on the nature of the active substance no carriersare, however, usually required in the case of soft gelatin capsules.Suitable carriers for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar, glucose and the like.Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and thelike, can be used for aqueous injection solutions of water-soluble saltsof compounds of formula I, but as a rule are not necessary. Suitablecarriers for suppositories are, for example, natural or hardened oils,waxes, fats, semi-liquid or liquid polyols and the like.

[0084] In addition, the pharmaceutical compositions can containpreservatives, solubilizers, stabilizers, wetting agents, emulsifiers,sweeteners, colorants, flavorants, salts for varying the osmoticpressure, buffers, masking agents or antioxidants. They can also containstill other therapeutically valuable substances.

[0085] As mentioned earlier, pharmaceutical compositions containing acompound of formula IA or IB or pharmaceutically acceptable saltsthereof and a therapeutically inert excipient are also an object of thepresent invention, as is a process for the production of suchpharmaceutical compositions which comprises bringing a therapeuticallyeffective amount of one or more compounds of formula IA or IB orpharmaceutically acceptable salts thereof and, if desired, one or moreother therapeutically valuable substances into a galenical dosage formtogether with one or more therapeutically inert carriers.

[0086] The dosage can vary within wide limits and will, of course, befitted to the individual requirements in each particular case. Ingeneral, the effective dosage for oral or parenteral administration isbetween 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day beingpreferred for all of the indications described. The daily dosage for anadult human being weighing 70 kg accordingly lies between 0.7-1400 mgper day, preferably between 7 and 700 mg per day.

EXAMPLES General Procedure A

[0087] Synthesis of 2-substituted 3-phenylamino-acrylonitriles

[0088] Potassium-tert-butylate (1 eq.) is added to a cooled (10° C.)solution of 3-phenylamino-propionitrile (1 eq.) and an aldehyde (1 eq.)in DMSO (approx. 0.3M). After stirring for 3 hours at r.t., the mixtureis cooled in an ice bath and water is added. The mixture is extractedseveral times with diethylether, the combined organic phases are driedover MgSO₄, and most of the solvent is evaporated under reducedpressure. The 2-substituted 3-phenylamino-acrylonitrile crystallizesfrom the remaining solvent and is sufficiently pure for furtherconversion according to general procedure B.

General Procedure B

[0089] Synthesis of 5-substituted 4-amino-pyrimidine-2-thiols

[0090] A catalytic amount (e.g. 0.1 eq.) of sodium ethoxide is added toa solution of 2-substituted 3-phenylamino-acrylonitrile (1 eq.) asprepared according to general procedure A and thiourea (1.1 eq.) inethanol which is then heated to reflux. After 6h, a drop of formic acidis added and approximately half of the solvent is evaporated underreduced pressure. The mixture is then placed in a refrigerator (4° C.)overnight. The precipitated 5-substituted

[0091] 4-amino-pyrimidine-2-thiol is collected and purified, e.g. bycrystallisation from EtOH or by column chromatography.

General Procedure C

[0092] Synthesis of 5-substituted 2-Alkylsulfanyl-pyrimidin-4-ylamines

[0093] 5-substituted 4-amino-pyrimidine-2-thiol is dissolved in 1Msodium methoxide solution in methanol or IM sodium ethoxide solution inethanol (1 eq.). After addition of an alkyl halide (2 eq.), the mixtureis stirred for 90 min at r.t. Formic acid (1 eq.) is added and the5-substituted 2-alkylsulfanyl-pyrimidin-4-ylamine is isolated from themixture, e.g. by HPLC chromatography (YMC CombiPrep C18 column 50×20 mm,solvent gradient 10-95% CH₃CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm,flow rate 40 ml/min).

[0094] Unless stated to the contrary, all of the examples listed belowwere prepared and characterized as described.

Example 1

[0095] (4-Amino-5-thiophen-2-ylmethyl-pyrimidin-2-ylsulfanyl)-aceticAcid Methyl Ester

[0096] Following general procedures A, B, and C, the title compound, MS:m/e=295.7 (M+H⁺), was prepared using 2-thiophenecarbaldehyde and methylbromoacetate.

Example 2

[0097] (4-Amino-5-thiophen-2-ylmethyl-pyrimidin-2-ylsulfanyl)-aceticAcid Ethyl Ester

[0098] Following general procedures A, B, and C, the title compound, MS:m/e=309.7 (M+H⁺), was prepared using 2-thiophenecarbaldehyde and ethylbromoacetate.

Example 3

[0099] (4-Amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic Acid Ethyl Ester

[0100] Following general procedures A, B, and C, the title compound, MS:m/e=303.8 (M+H⁺), was prepared using benzaldehyde and ethylbromoacetate.

Example 4

[0101][4-Amino-5-(1-methyl-1H-pyrrol-2-ylmethyl)-pyrimidin-2-ylsulfanyl]-aceticAcid Ethyl Ester

[0102] Following general procedures A, B, and C, the title compound, MS:m/e=306.8 (M+H⁺), was prepared using 1-methylpyrrole-2-carboxaldehydeand ethyl bromoacetate.

Example 5

[0103] [4-Amino-5-(2,4-dichloro-phenyl)-pyrimidin-2-ylsulfanyl]-aceticAcid Ethyl Ester

[0104] 2-(2,4-Dichloro-phenyl)-3-piperidin-1-yl-acrylonitrile

[0105] 2-(2,4-Dichloro-phenyl)-3-piperidin-1-yl-acrylonitrile wasprepared according to the method as described in Tetrahedron 1972, 28,1343.

[0106] 4-Amino-5-(2,4-dichloro-phenyl)-pyrimidin-2-ylsulfanyl]-aceticAcid Ethyl Ester

[0107] Following general procedures B and C, the title compound, MS:m/e=358.0 (M+H⁺), was prepared using 2-(2,4-dichloro-phenyl)-3-piperidin-1-yl-acrylonitrile and ethyl bromoacetate.

Example 6

[0108] [4-Amino-5-(4-bromo-benzyl)-pyrimidin-2-ylsulfanyl]-acetic AcidEthyl Ester

[0109] Following general procedures A, B, and C, the title compound, MS:m/e=382.0 (M+H⁺), was prepared using 4-bromobenzaldehyde and ethylbromoacetate.

Example 7

[0110]2-(4-Amino-5-thiophen-2-ylmethyl-pyrimidin-2-ylsulfanyl)-propionic AcidMethyl Ester

[0111] Following general procedures A, B, and C, the title compound, MS:m/e=310.2 (M+H⁺), was prepared using 2-thiophenecarbaldehyde and2-bromo-propionic acid methyl ester.

Example 8

[0112] 2-Prop-2-ynylsulfanyl-5-thiophen-2-ylmethyl-pyrimidin-4-ylamine

[0113] Following general procedures A, B, and C, the title compound, MS:m/e=262.0 (M+H^(°)), was prepared using 2-thiophenecarbaldehyde andpropargyl bromide.

Example 9

[0114] 2-Allylsulfanyl-5-thiophen-2-ylmethyl-pyrimidin-4-ylamine

[0115] Following general procedures A, B, and C, the title compound, MS:m/e=264.0 (M+H⁺), was prepared using 2-thiophenecarbaldehyde and allylbromide.

Example 10

[0116]2-Cyclopropylmethylsulfanyl-5-thiophen-2-ylmethyl-pyrimidin-4-ylamine

[0117] Following general procedures A, B, and C, the title compound, MS:m/e=278.0 (M+H⁺), was prepared using 2-thiophenecarbaldehyde andbromomethyl-cyclopropane.

Example 11

[0118]2-([1,2,4]Oxadiazol-3-ylmethylsulfanyl)-5-thiophen-2-ylmethyl-pyrimidin-4-ylamine

[0119] Following general procedures A, B, and C, the title compound, MS:m/e=306.0 (M+H⁺), was prepared using 2-thiophenecarbaldehyde and3-chloromethyl-[1,2,4] oxadiazole.

Example 12

[0120] (4-Amino-5-thiophen-3-ylmethyl-pyrimidin-2-ylsulfanyl)-aceticAcid Ethyl Ester

[0121] Following general procedures A, B, and C, the title compound, MS:m/e=310.0 (M+H⁺), was prepared using 3-thiophenecarbaldehyde and ethylbromoacetate.

Example 13

[0122] (4-Amino-5-furan-3-ylmethyl-pyrimidin-2-ylsulfanyl)-acetic AcidEthyl Ester

[0123] Following general procedures A, B, and C, the title compound, MS:m/e=294.0 (M+H⁺), was prepared using 3-furancarbaldehyde and ethylbromoacetate.

Example 14

[0124] [4-Amino-5-(3-methyl-thiophen-2-ylmethyl)-pyrimidin-2-ylsulfanyl]-acetic Acid Ethyl Ester

[0125] Following general procedures A, B, and C, the title compound, MS:m/e=324.0 (M+H⁺), was prepared using 3-methyl-thiophene-2-carbaldehydeand ethyl bromoacetate.

Example 15

[0126][4-Amino-5-(5-chloro-thiophen-2-ylmethyl)-pyrimidin-2-ylsulfanyl]-aceticAcid Ethyl Ester

[0127] Following general procedures A, B, and C, the title compound, MS:m/e=344.0 (M+H⁺), was prepared using 5-chloro-thiophene-2-carbaldehydeand ethyl bromoacetate.

Example 16

[0128][4-Amino-5-(5-ethyl-furan-2-ylmethyl)-pyrimidin-2-ylsulfanyl]-aceticAcid Ethyl Ester

[0129] Following general procedures A, B, and C, the title compound, MS:m/e=322.0 (M+H⁺), was prepared using 5-ethyl-furan-2-carbaldehyde andethyl bromoacetate.

Example 17

[0130][4-Amino-5-(5-methyl-furan-2-ylmethyl)-pyrimidin-2-ylsulfanyl]-aceticAcid Ethyl Ester

[0131] Following general procedures A, B, and C, the title compound, MS:m/e=308.0 (M+H⁺), was prepared using 5-methyl-furan-2-carbaldehyde andethyl bromoacetate.

Example 18

[0132] 4-(2-Allylsulfanyl-4-amino-pyrimidin-5-ylmethyl)-benzonitrile

[0133] Following general procedures A, B, and C, the title compound, MS:m/e=283.0 (M+H⁺), was prepared using 4-formyl-benzonitrile and allylbromide.

Example 19

[0134] 4-Amino-2-ethoxycarbonylmethylsulfanyl-pyrimidine-5-carboxylicAcid Ethyl Ester

[0135] Following general procedures B and C, the title compound, MS:m/e=286.0 (M+H⁺), was prepared using ethyl2-cyano-3-(3-thienylamino)-acrylate and ethyl bromoacetate.

Example 20

[0136] [4-Amino-5-(2-chloro-phenyl)-pyrimidin-2-ylsulfanyl]-acetic AcidEthyl Ester

[0137] a) 2-(2-Chloro-phenyl)-3-piperidin-1-yl-acrylonitrile

[0138] 2-(2-Chloro-phenyl)-3-piperidin-1-yl-acrylonitrile was preparedin analogy to the method as described in Tetrahedron 1972, 28, 1343.

[0139] b) [4-Amino-5-(2-chloro-phenyl)-pyrimidin-2-ylsulfanyl]-aceticAcid Ethyl Ester

[0140] Following general procedures B and C, the title compound, MS:m/e=324.0 (M+H⁺), was prepared using2-(2-chloro-phenyl)-3-piperidin-1-yl-acrylonitrile and ethylbromoacetate.

Example 21

[0141](4-Ethylamino-5-thiophen-2-ylmethyl-pyrimidin-2-ylsulfanyl)-acetic AcidEthyl Ester

[0142] To a solution of(4-Amino-5-thiophen-2-ylmethyl-pyrimidin-2-ylsulfanyl)-acetic acid ethylester (0.5 mmol, 155 mg) as prepared in example 12 and acetaldehyde (0.6mmol, 27 mg) in 1.25 ml of DMF was added acetic acid (0.25 ml) andsodium cyanoborohydride (0.6 mmol, 38 mg) and the mixture was shaken fortwo days at r.t. The title compound, MS: m/e=338.2 (M+H⁺), was obtainedfrom the mixture by HPLC chromatography (YMC CombiPrep C18 column 50×20mm, solvent gradient 10-95% CH₃CN in 0.1% TFA(aq) over 6.0 min, λ=230nm, flow rate 40 ml/min).

Example 22

[0143] (4-Amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic Acid Allyl Ester

[0144] a) (4-Amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic Acid

[0145] (4-Amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid wasobtained from 4-amino-5-benzyl-pyrimidine-2-thiol in analogy to themethod in J. Org. Chem. 1956, 21, 567.4-Amino-5-benzyl-pyrimidine-2-thiol was prepared according to generalprocedures A and B using benzaldehyde.

[0146] b) (4-Amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic Acid AllylEster

[0147] (4-Amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid (0.25 mmol,69 mg), dicyclohexylcarbodiimide (0.3 mmol, 62 mg) and allyl alcohol(0.3 mmol, 18 mg) were dissolved in 1 ml of DMF, and a catalytic amountof 4-dimethylaminopyridine (approx. 1-3 mg) was added. After shaking themixture for 24h at r.t., the title compound, MS: m/e=316.2 (M+H⁺), wasobtained from the reaction mixture by HPLC chromatography (YMC CombiPrepC18 column 50×20 mm, solvent gradient 10-95% CH₃CN in 0.1% TFA(aq) over6.0 min, λ=230 nm, flow rate 40 ml/min).

Example 23

[0148] (4-Amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid prop-2-ynylEster

[0149] The title compound, MS: m/e=314.0 (M+H⁺), was prepared frompropargyl alcohol in analogy to the method described in example 22.

Example 24

[0150] (4-Amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid2-methyl-cyclopropylmethyl Ester

[0151] The title compound, MS: m/e=343.9 (M+H⁺), was prepared from(2-methyl-cyclopropyl)-methanol in analogy to the method described inexample 22.

Example 25

[0152] (4-Amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic AcidCyclobutylmethyl Ester

[0153] a) Cyclobutylmethanol

[0154] Cyclobutylmethanol was prepared according to the method asdescribed in J. Chem. Soc. Perkin Trans. 1; 1993; 7, 801-804.

[0155] b) 4-Amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic AcidCyclobutylmethyl Ester

[0156] The title compound, MS: m/e=343.9 (M+H⁺), was prepared fromcyclobutylmethanol in analogy to the method described in example 22.

Example 26

[0157] (4-Amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic Acid CyclobutylEster

[0158] The title compound, MS: m/e=330.0 (M+H⁺), was prepared fromcyclobutanol in analogy to the method described in example 22.

Example 27

[0159] (4-Amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic Acid CyclopentylEster

[0160] The title compound, MS: m/e=344.0 (M+H⁺), was prepared fromcyclopentanol in analogy to the method described in example 22.

Example 28

[0161] (4-Amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid5-methyl-isoxazol-3-ylmethyl Ester

[0162] The title compound, MS: m/e=371.0 (M+H⁺), was prepared from(5-Methyl-isoxazol-3-yl)-methanol in analogy to the method described inexample 22.

Example 29

[0163] (4-Amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic AcidCyclopropylmethyl Ester

[0164] The title compound, MS: m/e=330.0 (M+H⁺), was prepared fromcyclopropylmethanol in analogy to the method described in example 22.

Example 30

[0165] (4-Amino-5-benzyl-pyrimidin-2-yloxy)-acetic Acid Methyl Ester

[0166] Following general procedures A, B, and C, the title compound, MS:m/e=274.0 (M+H⁺), was prepared using benzaldehyde and methylbromoacetate.

Example 31

[0167]4-Isobutylamino-5-thiophen-2-ylmethyl-pyrimidin-2-ylsulfanyl)-aceticAcid Ethyl Ester

[0168] The title compound, MS: m/e=366.0 (M+H⁺), was prepared in analogyto the method of example 21 from isobutyraldehyde.

Example 32

[0169] (4-Amino-5-cyclopropylmethyl-pyrimidin-2-ylsulfanyl)-acetic AcidEthyl Ester

[0170] Following general procedures A, B, and C, the title compound, MS:m/e=267.9 (M+H⁺), was prepared using cyclopropylcarbaldehyde and ethylbromoacetate.

Example 33

[0171]5-Benzyl-2-(3-cyclopropyl-[1,2,4]oxadiazol-5-ylmethylsulfanyl)-pyrimidin-4-ylamine

[0172] A solution of (4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-aceticacid (0.35 mg, 1.27 mmol) as prepared according to the method describedin example 22, and 1,1′-carbonyl-diimidazole (0.31 g, 1.91 mmol) in DMF(8 ml) was stirred at room temperature for 3 h and subsequentlyN-hydroxy-cyclopropanecarboxamidine (0.19 g, 1.91 mmol) was added. Thereaction mixture was stirred at 80° C. for 20 h and evaporated. Aceticacid (10 ml) was added and the stirred mixture was heated under refluxconditions for 2 h. Aqueous work-up, column chromatography on silica gel(ethyl acetate/hexane 3:2) and crystallization from ethyl acetate/hexaneyielded the title compound (36 mg, 9%) as an off-white solid, m.p. 94°C. and MS: m/e=340.3 (M+H⁺).

Example A

[0173] Tablets of the following composition are produced in aconventional manner: mg/Tablet Active ingredient 100  Powdered. lactose95 White corn starch 35 Polyvinylpyrrolidone  8 Na carboxymethylstarch10 Magnesium stearate  2 Tablet weight 250 

Example B

[0174] Tablets of the following composition are produced in aconventional manner: mg/Tablet Active ingredient 200 Powdered. lactose100 White corn starch  64 Polyvinylpyrrolidone  12 Nacarboxymethylstarch  20 Magnesium stearate  4 Tablet weight 400

Example C

[0175] Capsules of the following composition are produced: mg/CapsuleActive ingredient 50 Crystalline. lactose 60 Microcrystalline cellulose34 Talc  5 Magnesium stearate  1 Capsule fill weight 150 

[0176] The active ingredient having a suitable particle size, thecrystalline lactose and the microcrystalline cellulose are homogeneouslymixed with one another; sieved and thereafter talc and magnesiumstearate are admixed. The final mixture is filled into hard gelatincapsules of suitable size.

1.

wherein R¹ is selected from the group consisting of C₂-C₆-alkenyl,C₂-C₆-alkinyl, C₃-C₆-cycloalkyl, —C(O)O—(C₁-C₆)-alkyl,—C(O)O—(C₂-C₆)-alkenyl, —C(O)O—(C₂-C₆)-alkinyl,—C(O)O—(C₃-C₆)-cycloalkyl —C(O)O—CH₂-(C₃-C₆)-cycloalkyl,—C(O)O—(C₃-C₆)-cycloalkyl substituted by at least one (C₁-C₆)-alkyl,—C(O)O—CH₂-(C₃-C₆)-cycloalkyl substituted by at least one (C₁-C₆)-alkyl,—C(O)O—CH₂-heteroaryl, and —C(O)O—CH₂-heteroaryl substituted by at leastone substituent selected from the group consisting of C₁-C₆-alkyl,unsubstituted heteroaryl, and heteroaryl substituted by at least onesubstituent selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₃-C₆-cycloalkyl and halogen; R² isselected from the group consisting of hydrogen and C₁-C₆-alkyl; R³ isselected from the group consisting of unsubstituted aryl, arylsubstituted by at least one substituent selected from the groupconsisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl,C₃-C₆-cycloalkyl, halogen, and cyano, unsubstituted heteroaryl andheteroaryl substituted by at least one substituent selected from thegroup consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl,C₃-C₆-cycloalkyl, halogen, cyano, and —C(O)O—(C₁-C₆)-alkyl; R⁴ isselected from the group consisting of hydrogen and C₁-C₆-alkyl; and m is0, 1 or 2; or a pharmaceutically acceptable salt thereof.
 2. A compoundof formula I according to claim 1, wherein m is 0 or
 1. 3. A compound offormula I according to claim 1, wherein m is
 1. 4. A compound of formulaI according to claim 3, wherein R³ is unsubstituted heteroaryl orheteroaryl substituted by at least one substituent selected from thegroup consisting Of C₁-C6-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl,C3-C6-cycloalkyl, halogen and cyano.
 5. A compound of formula Iaccording to claim 4, wherein R¹ is selected from the group consistingof —C(O)O—(C₁-C₆)-alkyl, —C(O)O—(C₂-C₆)-alkenyl, —C(O)O—(C₂-C₆)-alkinyl,—C(O)O—(C₃-C₆)-cycloalkyl, —C(O)O—CH₂-(C₃-C₆)-cycloalkyl,—C(O)O—(C₃-C₆)-cycloalkyl or —C(O)O—CH₂-(C₃-C₆)-cycloalkyl substitutedby at least one C₁-C₆-alkyl, —C(O)O—CH₂-heteroaryl andC(O)O—CH₂-heteroaryl substituted by at least one C₁-C₆-alkyl.
 6. Acompound of formula I according to claim 5, selected from the groupconsisting of(4-amino-5-thiophen-2-ylmethyl-pyrimidin-2-ylsulfanyl)-acetic acidmethyl ester, (4-amino-5-thiophen-2-ylmethyl-pyrimidin-2-ylsulfanyl)-acetic acid ethyl ester,[4-amino-5-(1-methyl-1H-pyrrol-2-ylmethyl)-pyrimidin-2-ylsulfanyl]-aceticacid ethyl ester,2-(4-amino-5-thiophen-2-ylmethyl-pyrimidin-2-ylsulfanyl)-propionic acidmethyl ester,(4-amino-5-thiophen-3-ylmethyl-pyrimidin-2-ylsulfanyl)-acetic acid ethylester, (4-amino-5-furan-3-ylmethyl-pyrimidin-2-ylsulfanyl)-acetic acidethyl ester,[4-amino-5-(3-methyl-thiophen-2-ylmethyl)-pyrimidin-2-ylsulfanyl]-aceticacid ethyl ester,[4-amino-5-(5-chloro-thiophen-2-ylmethyl)-pyrimidin-2-ylsulfanyl]-aceticacid ethyl ester,[4-amino-5-(5-ethyl-furan-2-ylmethyl)-pyrimidin-2-ylsulfanyl]-aceticacid ethyl ester,[4-amino-5-(5-methyl-furan-2-ylmethyl)-pyrimidin-2-ylsulfanyl]-aceticacid ethyl ester,(4-ethylamino-5-thiophen-2-ylmethyl-pyrimidin-2-ylsulfanyl)-acetic acidethyl ester, and(4-isobutylamino-5-thiophen-2-ylmethyl-pyrimidin-2-ylsulfanyl)-aceticacid ethyl ester.
 7. A compound of formula I according to claim 4,wherein R¹ is unsubstituted heteroaryl or heteroaryl substituted by atleast one substituent selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C6-alkinyl, C₃-C₆-cycloalkyl or halogen.
 8. A compoundof formula I according to claim 7, 2-([1,2,4]oxadiazol-3-ylmethylsulfanyl)-5-thiophen-2-ylmethyl-pyrimidin-4-ylamine.9. A compound of formula I according to claim 4, wherein R¹ is selectedfrom the group consisting of C₂-C₆-alkenyl, C₂-C₆-alkinyl andC₃-C₆-cycloalkyl.
 10. A compound of formula I according to claim 9,selected from the group consisting of2-prop-2-ynylsulfanyl-5-thiophen-2-ylmethyl-pyrimidin-4-ylamine,2-allylsulfanyl-5-thiophen-2-ylmethyl-pyrimidin-4-ylamine, and2-cyclopropylmethylsulfanyl-5-thiophen-2-ylmethyl-pyrimidin-4-ylamine.11. A compound of formula I according to claim 3, wherein R³ isunsubstituted aryl or aryl substituted by at least one substituentselected from the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkinyl, C₃-C₆-cycloalkyl, halogen and cyano.
 12. A compound offormula I according to claim 11, wherein R¹ is selected from the groupconsisting of —C(O)O—(C₁-C₆)-alkyl, —C(O)O—(C₂-C₆)-alkenyl,—C(O)O—(C₂-C₆)-alkinyl, —C(O)O—(C₃-C₆)-cycloalkyl,—C(O)O—CH₂-(C₃-C₆)-cycloalkyl, —C(O)O—(C₃-C₆)-cycloalkyl or—C(O)O—CH₂-(C₃-C₆)-cycloalkyl substituted by at least one C₁-C₆-alkyl,—C(O)O—CH₂-heteroaryl and —C(O)O—CH₂-heteroaryl substituted by at leastone C₁-C₆-alkyl.
 13. A compound of formula I according to claim 12,selected from the group consisting of(4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid ethyl ester,[4-amino-5-(4-bromo-benzyl)-pyrimidin-2-ylsulfanyl]-acetic acid ethylester, (4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid allylester, (4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid prop-2-ynylester, (4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid2-methyl-cyclopropylmethyl ester,(4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid cyclobutylmethylester, (4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid cyclobutylester, (4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid cyclopentylester, (4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid5-methyl-isoxazol-3-ylmethyl ester,(4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid cyclopropylmethylester, and (4-amino-5-benzyl-pyrimidin-2-yloxy)-acetic acid methylester.
 14. A compound of formula I according to claim 11, wherein R¹ isunsubstituted heteroaryl or heteroaryl substituted by at least onesubstituent selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₃-C₆-cycloalkyl and halogen.
 15. Acompound of formula I according to claim 14,5-benzyl-2-(3-cyclopropyl-[1,2,4]oxadiazol-5-ylmethylsulfanyl)-pyrimidin-4-ylamine.16. A compound of formula I according to claim 11, wherein R¹ isselected from the group consisting of C₂-C₆-alkenyl, C₂-C₆-alkinyl andC₃-C₆-cycloalkyl.
 17. A compound of formula I according to claim 16,4-(2-allylsulfanyl-4-amino-pyrimidin-5-ylmethyl) -benzonitrile.
 18. Acompound of formula I according to claim 3, wherein R³ isC₃-C₆-cycloalkyl.
 19. A compound of formula I according to claim 18,(4-amino-5-cyclopropylmethyl-pyrimidin-2-ylsulfanyl)-acetic acid ethylester.
 20. A compound of formula I according to claim 1, wherein m is 0and R¹ is selected from the group consisting of —C(O)O—(C₁-C₆)-alkyl,—C(O)O—(C₂-C₆)-alkenyl, —C(O)O—(C₂-C₆)-alkinyl,—C(O)O—(C₃-C₆)-cycloalkyl, —C(O)O—CH₂-(C₃-C₆)-cycloalkyl,—C(O)O—(C₃-C₆)-cycloalkyl substituted by at least one C₁-C₆-alkyl,—C(O)O—CH₂-(C₃-C₆)-cycloalkyl substituted by at least one C₁-C₆-alkyl,—C(O)O—CH₂-heteroaryl and —C(O)O—CH₂-heteroaryl substituted by at leastone C₁-C₆-alkyl.
 21. A compound of formula I according to claim 20,selected from the group consisting o f[4-amino-5-(2,4-dichloro-phenyl)-pyrimidin-2-ylsulfanyl]-acetic acidethyl ester,4-amino-2-ethoxycarbonylmethylsulfanyl-pyrimidine-5-carboxylic acidethyl ester, and [4-amino-5-(2-chloro-phenyl)-pyrimidin-2-ylsulfanyl]-acetic acid ethyl ester.
 22. A compound offormula I according to claim 1, wherein R ² is hydrogen.
 23. A compoundof formula I according to claim 1, wherein R⁴ is hydrogen.
 24. A processfor the manufacture of a compound of formula I, claim 1, or apharmaceutically acceptable salt thereof, comprising reacting a compoundof formula

wherein R⁵ is selected from the group consisting of phenylamino,3-thienylamino and morpholino, with thiourea forming a compound offormula

reacting this compound with a compound of formula

wherein X is halogen, converting the amino group into an aminoalkylgroup, thereby forming a compound of formula

and, converting a compound of formula I into a pharmaceuticallyacceptable salt.
 25. A pharmaceutical composition comprising atherapeutically effective amount of at least one compound of formula Iaccording to claim 1, and at least one pharmaceutically acceptableexcipient.
 26. A method for the treatment and prevention of anxietycomprising administering a therapeutically effective amount of acompound of formula I according to claim 1, or a pharamceuticallyacceptable salt thereof, to a patient in need of such treatment.
 27. Amethod for the treatment of chronic and acute pain comprisingadministering a therapeutically effective amount of a compound offormula I according to claim 1, or a pharmaceutically acceptable saltthereof, to a patient in need of such treatment.